Page 20 - JCTR-11-2

Journal of Clinical and
Translational Research US-mediated drug delivery

MPTP) 105-112 and transgenic (i.e., overexpression of the clearance of various forms of α-synuclein, reducing
α-synuclein gene). 113-116 rodent or non-human primate neuronal loss, restoring dopamine secretion, and improving
models of PD. These therapies primarily aim to protect motor deficits in PD mice (Table 6).
dopaminergic neurons from neurotoxicity by activating In conclusion, MB-assisted MRgFUS is an effective and
cell growth and survival, autophagy, clearance of safe modality for delivering innovative therapeutics for the
alpha-synuclein, or by inhibiting oxidative stress, treatment of PD.
neuroinflammation, and apoptosis. Therapeutics tested
include glial cell line-derived neurotrophic factor 6.3. Clinical phase
(GDNF), 105-107,109 brain-derived neurotrophic factor,
110
neurturin, curcumin, triptolide (T10), gastrodin, The first two clinical studies investigated the feasibility
108
113
109
112
and a short hairpin RNA (shRNA) against α-synuclein. 114 and safety of BBB opening in PD patients using a bolus
of Luminity MBs (4 µL/kg) and the ExAblate Neuro
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Preclinical studies have investigated MB-assisted MRgFUS system. 117,118 In the study of Gasca-Salas
MRgUS protocols for delivering the GDNF gene (through et al., patients underwent two treatments, separated
117
plasmid DNA or AAV vectors) to various brain regions by a 3 – 3-week interval, to permeabilize the BBB at the
including the striatum, substantia nigra, caudate-putamen, level of the right parieto-occipito-temporal cortex. BBB
and ventral midbrain in rodent models of PD. 105-107,109,110 opening was monitored through DCE-MRI for 24 h
Plasmids encoding GDNF were generally loaded onto and 7 days post-treatment. Neuropsychological and
MBs to protect them from enzymatic degradation in the motor evaluations, as well as 18F-FDG and 18F-FMT
bloodstream. 105-107,110 In contrast, the AAV-GDNF vector PET imaging, were conducted 3 – 4 weeks after the final
was co-administered with MBs before US exposure. treatment. This study demonstrated that BBB opening in
109
These studies demonstrated successful GDNF expression in PD patients was both reversible and safe, with no reported
targeted brain regions, attenuating damage to nigrostriatal side effects. Similarly, Pineda-Pardo et al. investigated
118
dopaminergic pathways and even rescuing dopaminergic uni- and bilateral BBB opening in the posterior putamen
109
neuronal loss. 107,109,110 This neuroprotective strategy also using the same MB-assisted MRgFUS protocol as Gasca-
improved motor-related behavioral deficits. 105-107,109,110 Salas et al. Similar conclusions were drawn, confirming the
Due to its critical role in PD pathology, α-synuclein safety and feasibility of the approach. 117
has been a primary target for therapeutic strategies In 2024, Gasca-Salas et al. expanded on their earlier
119
such as shRNA against α-synuclein and triptolide. work by demonstrating that BBB opening in the substantia
114
113
Xhima et al. used MB-assisted US to deliver an AAV9 nigra and putamen in PD patients was well tolerated,
114
vector encoding shRNA targeting α-synuclein into the reversible, and feasible. In this study, Luminity MBs
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hippocampus, substantia nigra, olfactory bulb, and (2.5 mL/min) were infused using the same protocol. In
dorsal motor nucleus in a transgenic PD mouse model. addition, Huang et al. further evaluated the ExAblate
120
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After i.v. administration of Definity MBs (0.02 mL/kg), Neuro MRgFUS system’s cavitation feedback controller for
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the targeted brain regions were exposed to US waves active power modulation during unilateral targeting of the
(lab-made MRgFUS device; 10 ms bursts, 1 Hz PRF) for putamen in PD patients. Definity MBs (4 µL/kg/5 min)
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120 s. This approach significantly reduced α-synuclein were infused, and a cavitation emission-based feedback
expression in the targeted areas, although no changes were controller automatically adjusted the acoustic power to
observed in other neuronal biomarkers (e.g., tyrosine maintain the desired cavitation dose levels. The efficacy
hydroxylase, synaptophysin), glial activation, or cell death. of BBB opening was assessed with DCE-MRI and
However, this study did not analyze behavioral or cognitive hemorrhages were monitored with T2*-weighted MRI.
outcomes, which warrants further investigation. As for the Results demonstrated that such a device enabled efficient
tripolide treatment, Feng et al. explored MB-assisted and safe BBB opening by dynamically modulating acoustic
113
FUS for delivering this drug to the substantia nigra in a power.
transgenic PD mouse model. Triptolide, an autophagy
inducer, alleviates autophagic dysfunction associated In another study, Meng et al. investigated the
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with the accumulation of α-synuclein in PD. MBs loaded safety and feasibility of delivering recombinant
with triptolide targeted the BBB and accumulated at the glucocerebrosidase (GCase) to the putamen of PD patients
endothelial wall of cerebral vessels. US waves (lab-made with GBA1 mutations using MB-assisted MRgFUS. The
US device; 10 ms burst length, 0.3, 0.45, and 0.8 MPa, GCase enzyme, encoded by the GBA1 gene, is inversely
1 Hz PRF) were applied to the substantia nigra for 60 s related to α-synuclein oligomer accumulation. Its cerebral
after i.v. MB injection. This resulted in increased triptolide deficit in GBA1-related and idiopathic PD is associated
concentrations in the targeted brain region, facilitating with disease severity. In this study, patients underwent

Volume 11 Issue 2 (2025) 14 doi: 10.36922/jctr.24.00061